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1.
Recurso na Internet em Inglês, Espanhol | LIS - Localizador de Informação em Saúde | ID: lis-LISBR1.1-46987

RESUMO

The Pan American Health Organization has updated an alert to its member countries on the Novel Coronavirus (nCoV), recommending that they strengthen surveillance activities to detect patients with acute respiratory disease, and that “health care workers have access to up to date information on the illness, be familiar with the principles and procedures for handling nCoV infections, and be trained to consult a patient’s travel history to link this information with clinical data.”


Assuntos
Vírus da SARS , Coronavírus da Síndrome Respiratória do Oriente Médio , Controle de Doenças Transmissíveis , Infecções por Coronavirus
2.
Recurso na Internet em Inglês, Espanhol, Português | LIS - Localizador de Informação em Saúde | ID: lis-LISBR1.1-46976

RESUMO

Em 30 de janeiro de 2020, a OMS declarou que o surto do novo coronavírus (2019-nCoV) constitui uma Emergência de Saúde Pública de Importância Internacional (ESPII).


Assuntos
Coronavírus da Síndrome Respiratória do Oriente Médio , Vírus da SARS , Coronavirus
3.
Recurso na Internet em Português | LIS - Localizador de Informação em Saúde, LIS-bvsms | ID: lis-LISBR1.1-46980

RESUMO

Em 30 de janeiro de 2020, a OMS declarou que o surto do novo coronavírus (2019-nCoV) constitui uma Emergência de Saúde Pública de Importância Internacional (ESPII).


Assuntos
Infecções por Coronavirus , Coronavírus da Síndrome Respiratória do Oriente Médio , Betacoronavirus , Vírus da SARS
4.
5.
Recurso na Internet em Português | LIS - Localizador de Informação em Saúde, LIS-bvsms | ID: lis-LISBR1.1-46947

RESUMO

Site da OPAS Brasil - em 20 de janeiro de 2020 – Emitiu um alerta aos seus países membros sobre o novo coronavírus (nCoV).


Assuntos
Coronavirus/patogenicidade , Vírus da SARS/patogenicidade
7.
J Enzyme Inhib Med Chem ; 35(1): 145-151, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31724441

RESUMO

There were severe panics caused by Severe Acute Respiratory Syndrome (SARS) and Middle-East Respiratory Syndrome-Coronavirus. Therefore, researches targeting these viruses have been required. Coronaviruses (CoVs) have been rising targets of some flavonoids. The antiviral activity of some flavonoids against CoVs is presumed directly caused by inhibiting 3C-like protease (3CLpro). Here, we applied a flavonoid library to systematically probe inhibitory compounds against SARS-CoV 3CLpro. Herbacetin, rhoifolin and pectolinarin were found to efficiently block the enzymatic activity of SARS-CoV 3CLpro. The interaction of the three flavonoids was confirmed using a tryptophan-based fluorescence method, too. An induced-fit docking analysis indicated that S1, S2 and S3' sites are involved in binding with flavonoids. The comparison with previous studies showed that Triton X-100 played a critical role in objecting false positive or overestimated inhibitory activity of flavonoids. With the systematic analysis, the three flavonoids are suggested to be templates to design functionally improved inhibitors.


Assuntos
Antivirais/farmacologia , Inibidores Enzimáticos/farmacologia , Flavonoides/farmacologia , Vírus da SARS/efeitos dos fármacos , Proteínas Virais/antagonistas & inibidores , Antivirais/síntese química , Antivirais/química , Cisteína Endopeptidases/isolamento & purificação , Cisteína Endopeptidases/metabolismo , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Flavonoides/síntese química , Flavonoides/química , Humanos , Estrutura Molecular , Vírus da SARS/enzimologia , Relação Estrutura-Atividade , Proteínas Virais/isolamento & purificação , Proteínas Virais/metabolismo
8.
Emerg Microbes Infect ; 8(1): 1511-1523, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31631785

RESUMO

Interferons (IFNs) control viral infections by inducing expression of IFN-stimulated genes (ISGs) that restrict distinct steps of viral replication. We report herein that gamma-interferon-inducible lysosomal thiol reductase (GILT), a lysosome-associated ISG, restricts the infectious entry of selected enveloped RNA viruses. Specifically, we demonstrated that GILT was constitutively expressed in lung epithelial cells and fibroblasts and its expression could be further induced by type II interferon. While overexpression of GILT inhibited the entry mediated by envelope glycoproteins of SARS coronavirus (SARS-CoV), Ebola virus (EBOV) and Lassa fever virus (LASV), depletion of GILT enhanced the entry mediated by these viral envelope glycoproteins. Furthermore, mutations that impaired the thiol reductase activity or disrupted the N-linked glycosylation, a posttranslational modification essential for its lysosomal localization, largely compromised GILT restriction of viral entry. We also found that the induction of GILT expression reduced the level and activity of cathepsin L, which is required for the entry of these RNA viruses in lysosomes. Our data indicate that GILT is a novel antiviral ISG that specifically inhibits the entry of selected enveloped RNA viruses in lysosomes via disruption of cathepsin L metabolism and function and may play a role in immune control and pathogenesis of these viruses.


Assuntos
Ebolavirus/fisiologia , Doença pelo Vírus Ebola/imunologia , Febre Lassa/imunologia , Vírus Lassa/fisiologia , Oxirredutases atuantes sobre Doadores de Grupo Enxofre/imunologia , Vírus da SARS/fisiologia , Síndrome Respiratória Aguda Grave/imunologia , Proteínas do Envelope Viral/metabolismo , Internalização do Vírus , Catepsina L/genética , Catepsina L/imunologia , Linhagem Celular , Ebolavirus/genética , Doença pelo Vírus Ebola/genética , Doença pelo Vírus Ebola/virologia , Humanos , Febre Lassa/genética , Febre Lassa/virologia , Vírus Lassa/genética , Lisossomos/genética , Lisossomos/imunologia , Lisossomos/virologia , Oxirredutases atuantes sobre Doadores de Grupo Enxofre/genética , Vírus da SARS/genética , Síndrome Respiratória Aguda Grave/genética , Síndrome Respiratória Aguda Grave/virologia , Proteínas do Envelope Viral/genética , Replicação Viral
9.
Virus Genes ; 55(4): 545-549, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31076983

RESUMO

Bats have been widely known as natural reservoir hosts of zoonotic diseases, such as severe acute respiratory syndrome (SARS) and Middle East respiratory syndrome (MERS) caused by coronaviruses (CoVs). In the present study, we investigated the whole genomic sequence of a SARS-like bat CoV (16BO133) and found it to be 29,075 nt in length with a 40.9% G+C content. Phylogenetic analysis using amino acid sequences of the ORF 1ab and the spike gene showed that the bat coronavirus strain 16BO133 was grouped with the Beta-CoV lineage B and was closely related to the JTMC15 strain isolated from Rhinolophus ferrumequinum in China. However, 16BO133 was distinctly located in the phylogenetic topology of the human SARS CoV strain (Tor2). Interestingly, 16BO133 showed complete elimination of ORF8 regions induced by a frame shift of the stop codon in ORF7b. The lowest amino acid identity of 16BO133 was identified at the spike region among various ORFs. The spike region of 16BO133 showed 84.7% and 75.2% amino acid identity with Rf1 (SARS-like bat CoV) and Tor2 (human SARS CoV), respectively. In addition, the S gene of 16BO133 was found to contain the amino acid substitution of two critical residues (N479S and T487 V) associated with human infection. In conclusion, we firstly carried out whole genome characterization of the SARS-like bat coronavirus discovered in the Republic of Korea; however, it presumably has no human infectivity. However, continuous surveillance and genomic characterization of coronaviruses from bats are necessary due to potential risks of human infection induced by genetic mutation.


Assuntos
Betacoronavirus/isolamento & purificação , Quirópteros/virologia , Genoma Viral , Animais , Betacoronavirus/classificação , Betacoronavirus/genética , Humanos , Tipagem Molecular , Filogenia , República da Coreia , Vírus da SARS/genética , Análise de Sequência de Proteína , Especificidade da Espécie , Sequenciamento Completo do Genoma
10.
Nat Commun ; 10(1): 2342, 2019 05 28.
Artigo em Inglês | MEDLINE | ID: mdl-31138817

RESUMO

Recent history is punctuated by the emergence of highly pathogenic coronaviruses such as SARS- and MERS-CoV into human circulation. Upon infecting host cells, coronaviruses assemble a multi-subunit RNA-synthesis complex of viral non-structural proteins (nsp) responsible for the replication and transcription of the viral genome. Here, we present the 3.1 Å resolution structure of the SARS-CoV nsp12 polymerase bound to its essential co-factors, nsp7 and nsp8, using single particle cryo-electron microscopy. nsp12 possesses an architecture common to all viral polymerases as well as a large N-terminal extension containing a kinase-like fold and is bound by two nsp8 co-factors. This structure illuminates the assembly of the coronavirus core RNA-synthesis machinery, provides key insights into nsp12 polymerase catalysis and fidelity and acts as a template for the design of novel antiviral therapeutics.


Assuntos
Coenzimas/ultraestrutura , RNA Polimerases Dirigidas por DNA/ultraestrutura , Vírus da SARS/ultraestrutura , Proteínas não Estruturais Virais/ultraestrutura , Microscopia Crioeletrônica , Genoma Viral , Vírus da SARS/metabolismo
11.
Virol J ; 16(1): 69, 2019 05 27.
Artigo em Inglês | MEDLINE | ID: mdl-31133031

RESUMO

BACKGROUND: Coronaviruses (CoVs) primarily cause enzootic infections in birds and mammals but, in the last few decades, have shown to be capable of infecting humans as well. The outbreak of severe acute respiratory syndrome (SARS) in 2003 and, more recently, Middle-East respiratory syndrome (MERS) has demonstrated the lethality of CoVs when they cross the species barrier and infect humans. A renewed interest in coronaviral research has led to the discovery of several novel human CoVs and since then much progress has been made in understanding the CoV life cycle. The CoV envelope (E) protein is a small, integral membrane protein involved in several aspects of the virus' life cycle, such as assembly, budding, envelope formation, and pathogenesis. Recent studies have expanded on its structural motifs and topology, its functions as an ion-channelling viroporin, and its interactions with both other CoV proteins and host cell proteins. MAIN BODY: This review aims to establish the current knowledge on CoV E by highlighting the recent progress that has been made and comparing it to previous knowledge. It also compares E to other viral proteins of a similar nature to speculate the relevance of these new findings. Good progress has been made but much still remains unknown and this review has identified some gaps in the current knowledge and made suggestions for consideration in future research. CONCLUSIONS: The most progress has been made on SARS-CoV E, highlighting specific structural requirements for its functions in the CoV life cycle as well as mechanisms behind its pathogenesis. Data shows that E is involved in critical aspects of the viral life cycle and that CoVs lacking E make promising vaccine candidates. The high mortality rate of certain CoVs, along with their ease of transmission, underpins the need for more research into CoV molecular biology which can aid in the production of effective anti-coronaviral agents for both human CoVs and enzootic CoVs.


Assuntos
Coronavirus/química , Proteínas do Envelope Viral/química , Animais , Coronavirus/genética , Coronavirus/patogenicidade , Infecções por Coronavirus/virologia , Humanos , Vírus da SARS/química , Vírus da SARS/genética , Vírus da SARS/patogenicidade , Síndrome Respiratória Aguda Grave/virologia , Proteínas do Envelope Viral/genética , Zoonoses/transmissão , Zoonoses/virologia
12.
PLoS Comput Biol ; 15(3): e1006930, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30925168

RESUMO

There exists significant interest in developing statistical and computational tools for inferring 'who infected whom' in an infectious disease outbreak from densely sampled case data, with most recent studies focusing on the analysis of whole genome sequence data. However, genomic data can be poorly informative of transmission events if mutations accumulate too slowly to resolve individual transmission pairs or if there exist multiple pathogens lineages within-host, and there has been little focus on incorporating other types of outbreak data. We present here a methodology that uses contact data for the inference of transmission trees in a statistically rigorous manner, alongside genomic data and temporal data. Contact data is frequently collected in outbreaks of pathogens spread by close contact, including Ebola virus (EBOV), severe acute respiratory syndrome coronavirus (SARS-CoV) and Mycobacterium tuberculosis (TB), and routinely used to reconstruct transmission chains. As an improvement over previous, ad-hoc approaches, we developed a probabilistic model that relates a set of contact data to an underlying transmission tree and integrated this in the outbreaker2 inference framework. By analyzing simulated outbreaks under various contact tracing scenarios, we demonstrate that contact data significantly improves our ability to reconstruct transmission trees, even under realistic limitations on the coverage of the contact tracing effort and the amount of non-infectious mixing between cases. Indeed, contact data is equally or more informative than fully sampled whole genome sequence data in certain scenarios. We then use our method to analyze the early stages of the 2003 SARS outbreak in Singapore and describe the range of transmission scenarios consistent with contact data and genetic sequence in a probabilistic manner for the first time. This simple yet flexible model can easily be incorporated into existing tools for outbreak reconstruction and should permit a better integration of genomic and epidemiological data for inferring transmission chains.


Assuntos
Teorema de Bayes , Doenças Transmissíveis/transmissão , Biologia Computacional/métodos , Busca de Comunicante , Surtos de Doenças/estatística & dados numéricos , Genoma Viral/genética , Algoritmos , Doenças Transmissíveis/virologia , Humanos , Modelos Biológicos , Vírus da SARS/genética , Síndrome Respiratória Aguda Grave/transmissão , Síndrome Respiratória Aguda Grave/virologia , Singapura , Software
13.
J Vis Exp ; (145)2019 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-30882796

RESUMO

The protocol aims to generate coronavirus (CoV) spike (S) fusion protein pseudotyped particles with a murine leukemia virus (MLV) core and luciferase reporter, using a simple transfection procedure of the widely available HEK-293T cell line. Once formed and released from producer cells, these pseudovirions incorporate a luciferase reporter gene. Since they only contain the heterologous coronavirus spike protein on their surface, the particles behave like their native coronavirus counterparts for entry steps. As such, they are the excellent surrogates of native virions for studying viral entry into host cells. Upon successful entry and infection into target cells, the luciferase reporter gets integrated into the host cell genome and is expressed. Using a simple luciferase assay, transduced cells can be easily quantified. An important advantage of the procedure is that it can be performed in biosafety level 2 (BSL-2) facilities instead of BSL-3 facilities required for work with highly pathogenic coronaviruses such as Middle East respiratory syndrome coronavirus (MERS-CoV) and severe acute respiratory syndrome coronavirus (SARS-CoV). Another benefit comes from its versatility as it can be applied to envelope proteins belonging to all three classes of viral fusion proteins, such as the class I influenza hemagglutinin (HA) and Ebola virus glycoprotein (GP), the class II Semliki forest virus E1 protein, or the class III vesicular stomatitis virus G glycoprotein. A limitation of the methodology is that it can only recapitulate virus entry steps mediated by the envelope protein being investigated. For studying other viral life cycle steps, other methods are required. Examples of the many applications these pseudotype particles can be used in include investigation of host cell susceptibility and tropism and testing the effects of virus entry inhibitors to dissect viral entry pathways used.


Assuntos
Contenção de Riscos Biológicos , Coronavirus/patogenicidade , Animais , Células HEK293 , Humanos , Camundongos , Coronavírus da Síndrome Respiratória do Oriente Médio/patogenicidade , Vírus da SARS/patogenicidade , Glicoproteína da Espícula de Coronavírus/metabolismo , Vírion/patogenicidade , Internalização do Vírus/efeitos dos fármacos
14.
Infect Genet Evol ; 69: 224-229, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30735813

RESUMO

Bats are the natural reservoirs of severe acute respiratory syndrome coronavirus (SARS-CoV) which caused the outbreak of human SARS in 2002-2003. We introduce the genetic diversity of SARS-related coronaviruses (SARSr-CoVs) discovered in bats and provide insights on the bat origin of human SARS. We also analyze the viral geographical structure that may improve our understanding of the evolution of bat SARSr-CoVs.


Assuntos
Quirópteros/virologia , Filogenia , Filogeografia , Vírus da SARS/classificação , Vírus da SARS/genética , Animais , Reservatórios de Doenças/virologia , Evolução Molecular , Variação Genética , Genoma Viral , Geografia Médica , Humanos , Recombinação Genética , Síndrome Respiratória Aguda Grave/epidemiologia , Síndrome Respiratória Aguda Grave/transmissão , Síndrome Respiratória Aguda Grave/virologia
15.
Cell ; 176(5): 1026-1039.e15, 2019 02 21.
Artigo em Inglês | MEDLINE | ID: mdl-30712865

RESUMO

Recent outbreaks of severe acute respiratory syndrome and Middle East respiratory syndrome, along with the threat of a future coronavirus-mediated pandemic, underscore the importance of finding ways to combat these viruses. The trimeric spike transmembrane glycoprotein S mediates entry into host cells and is the major target of neutralizing antibodies. To understand the humoral immune response elicited upon natural infections with coronaviruses, we structurally characterized the SARS-CoV and MERS-CoV S glycoproteins in complex with neutralizing antibodies isolated from human survivors. Although the two antibodies studied blocked attachment to the host cell receptor, only the anti-SARS-CoV S antibody triggered fusogenic conformational changes via receptor functional mimicry. These results provide a structural framework for understanding coronavirus neutralization by human antibodies and shed light on activation of coronavirus membrane fusion, which takes place through a receptor-driven ratcheting mechanism.


Assuntos
Coronavirus/imunologia , Glicoproteína da Espícula de Coronavírus/metabolismo , Glicoproteína da Espícula de Coronavírus/ultraestrutura , Animais , Anticorpos Monoclonais/imunologia , Anticorpos Neutralizantes/imunologia , Anticorpos Antivirais/imunologia , Coronavirus/metabolismo , Infecções por Coronavirus/imunologia , Células HEK293 , Humanos , Imunidade Humoral/imunologia , Coronavírus da Síndrome Respiratória do Oriente Médio/imunologia , Coronavírus da Síndrome Respiratória do Oriente Médio/metabolismo , Mimetismo Molecular/imunologia , Ligação Proteica , Receptores Virais/metabolismo , Vírus da SARS/imunologia , Vírus da SARS/metabolismo , Glicoproteína da Espícula de Coronavírus/fisiologia , Células Vero , Internalização do Vírus
16.
Eur J Med Chem ; 167: 472-484, 2019 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-30784880

RESUMO

Since pyrithiobac (PTB) is a successful commercial herbicide with very low toxicity against mammals, it is worth exploring its derivatives for an extensive study. Herein, a total of 35 novel compounds were chemically synthesized and single crystal of 6-6 was obtained to confirm the molecular structure of this family of compounds. The novel PTB derivatives were fully evaluated against various biological platforms. From the bioassay results, the best AHAS inhibitor 6-22 displayed weaker herbicidal activity but stronger anti-Candida activity than PTB did. For plant pathogenic fungi, 6-26 showed excellent activity at 50 mg/L dosage. Preliminary insecticidal activity and antiviral activity were also observed for some title compounds. Strikingly, 6-5 exhibited a promising inhibitory activity against SARS-CoV Mpro with IC50 of 4.471 µM and a low cellular cytotoxicity against mammalian 293 T cells. Based on the results of molecular modeling, HOMO-1 was considered to be a factor that affects AHAS inhibition and a possible binding mode of 6-5 with SARS-CoV Mpro was predicted. This is the first time that PTB derivatives have been studied as biological agents other than herbicides. The present research hence has suggested that more attentions should be paid to compounds belonging to this family to develop novel agrochemicals or medicines.


Assuntos
Benzoatos/síntese química , Benzoatos/farmacologia , Fungos/efeitos dos fármacos , Herbicidas/síntese química , Acetolactato Sintase/antagonistas & inibidores , Antivirais/síntese química , Antivirais/farmacologia , Benzoatos/química , Desenho de Drogas , Herbicidas/farmacologia , Herbicidas/uso terapêutico , Modelos Moleculares , Estrutura Molecular , Vírus da SARS/efeitos dos fármacos
17.
Viruses ; 11(1)2019 01 14.
Artigo em Inglês | MEDLINE | ID: mdl-30646565

RESUMO

Coronaviruses (CoVs) have formerly been regarded as relatively harmless respiratory pathogens to humans. However, two outbreaks of severe respiratory tract infection, caused by the severe acute respiratory syndrome coronavirus (SARS-CoV) and the Middle East respiratory syndrome coronavirus (MERS-CoV), as a result of zoonotic CoVs crossing the species barrier, caused high pathogenicity and mortality rates in human populations. This brought CoVs global attention and highlighted the importance of controlling infectious pathogens at international borders. In this review, we focus on our current understanding of the epidemiology, pathogenesis, prevention, and treatment of SARS-CoV and MERS-CoV, as well as provides details on the pivotal structure and function of the spike proteins (S proteins) on the surface of each of these viruses. For building up more suitable animal models, we compare the current animal models recapitulating pathogenesis and summarize the potential role of host receptors contributing to diverse host affinity in various species. We outline the research still needed to fully elucidate the pathogenic mechanism of these viruses, to construct reproducible animal models, and ultimately develop countermeasures to conquer not only SARS-CoV and MERS-CoV, but also these emerging coronaviral diseases.


Assuntos
Infecções por Coronavirus/prevenção & controle , Coronavírus da Síndrome Respiratória do Oriente Médio/patogenicidade , Vírus da SARS/patogenicidade , Síndrome Respiratória Aguda Grave/prevenção & controle , Animais , China/epidemiologia , Quirópteros/virologia , Infecções por Coronavirus/tratamento farmacológico , Infecções por Coronavirus/epidemiologia , Modelos Animais de Doenças , Genoma Viral , Humanos , Camundongos , Oriente Médio/epidemiologia , Coronavírus da Síndrome Respiratória do Oriente Médio/genética , Vírus da SARS/genética , Síndrome Respiratória Aguda Grave/tratamento farmacológico , Síndrome Respiratória Aguda Grave/epidemiologia , Glicoproteína da Espícula de Coronavírus , Vacinas Virais/imunologia , Zoonoses/transmissão , Zoonoses/virologia
18.
Viruses ; 11(1)2019 01 09.
Artigo em Inglês | MEDLINE | ID: mdl-30634396

RESUMO

Bats are speculated to be reservoirs of several emerging viruses including coronaviruses (CoVs) that cause serious disease in humans and agricultural animals. These include CoVs that cause severe acute respiratory syndrome (SARS), Middle East respiratory syndrome (MERS), porcine epidemic diarrhea (PED) and severe acute diarrhea syndrome (SADS). Bats that are naturally infected or experimentally infected do not demonstrate clinical signs of disease. These observations have allowed researchers to speculate that bats are the likely reservoirs or ancestral hosts for several CoVs. In this review, we follow the CoV outbreaks that are speculated to have originated in bats. We review studies that have allowed researchers to identify unique adaptation in bats that may allow them to harbor CoVs without severe disease. We speculate about future studies that are critical to identify how bats can harbor multiple strains of CoVs and factors that enable these viruses to "jump" from bats to other mammals. We hope that this review will enable readers to identify gaps in knowledge that currently exist and initiate a dialogue amongst bat researchers to share resources to overcome present limitations.


Assuntos
Quirópteros/virologia , Coronavirus/fisiologia , Surtos de Doenças , Reservatórios de Doenças/veterinária , Animais , Doenças Assintomáticas , Coronavirus/patogenicidade , Infecções por Coronavirus , Reservatórios de Doenças/virologia , Evolução Molecular , Genoma Viral , Humanos , Filogenia , Vírus da SARS/patogenicidade , Vírus da SARS/fisiologia , Síndrome Respiratória Aguda Grave , Suínos
19.
J Virol ; 93(6)2019 03 15.
Artigo em Inglês | MEDLINE | ID: mdl-30626688

RESUMO

Transmembrane serine protease TMPRSS2 activates the spike protein of highly pathogenic human coronaviruses such as severe acute respiratory syndrome-related coronavirus (SARS-CoV) and Middle East respiratory syndrome-related coronavirus (MERS-CoV). In vitro, activation induces virus-cell membrane fusion at the cell surface. However, the roles of TMPRSS2 during coronavirus infection in vivo are unclear. Here, we used animal models of SARS-CoV and MERS-CoV infection to investigate the role of TMPRSS2. Th1-prone C57BL/6 mice and TMPRSS2-knockout (KO) mice were used for SARS-CoV infection, and transgenic mice expressing the human MERS-CoV receptor DPP4 (hDPP4-Tg mice) and TMPRSS2-KO hDPP4-Tg mice were used for MERS-CoV infection. After experimental infection, TMPRSS2-deficient mouse strains showed reduced body weight loss and viral kinetics in the lungs. Lack of TMPRSS2 affected the primary sites of infection and virus spread within the airway, accompanied by less severe immunopathology. However, TMPRSS2-KO mice showed weakened inflammatory chemokine and/or cytokine responses to intranasal stimulation with poly(I·C), a Toll-like receptor 3 agonist. In conclusion, TMPRSS2 plays a crucial role in viral spread within the airway of murine models infected by SARS-CoV and MERS-CoV and in the resulting immunopathology.IMPORTANCE Broad-spectrum antiviral drugs against highly pathogenic coronaviruses and other emerging viruses are desirable to enable a rapid response to pandemic threats. Transmembrane protease serine type 2 (TMPRSS2), a protease belonging to the type II transmembrane serine protease family, cleaves the coronavirus spike protein, making it a potential therapeutic target for coronavirus infections. Here, we examined the role of TMPRSS2 using animal models of SARS-CoV and MERS-CoV infection. The results suggest that lack of TMPRSS2 in the airways reduces the severity of lung pathology after infection by SARS-CoV and MERS-CoV. Taken together, the results will facilitate development of novel targets for coronavirus therapy.


Assuntos
Infecções por Coronavirus/imunologia , Infecções por Coronavirus/metabolismo , Pulmão/imunologia , Pulmão/metabolismo , Coronavírus da Síndrome Respiratória do Oriente Médio/imunologia , Serina Endopeptidases/metabolismo , Animais , Linhagem Celular , Infecções por Coronavirus/virologia , Modelos Animais de Doenças , Feminino , Humanos , Pulmão/virologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Transgênicos , Poli I-C/metabolismo , Vírus da SARS , Síndrome Respiratória Aguda Grave/imunologia , Síndrome Respiratória Aguda Grave/metabolismo , Síndrome Respiratória Aguda Grave/virologia , Glicoproteína da Espícula de Coronavírus/metabolismo , Receptor 3 Toll-Like/metabolismo , Células Vero
20.
Nat Rev Microbiol ; 17(3): 181-192, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30531947

RESUMO

Severe acute respiratory syndrome coronavirus (SARS-CoV) and Middle East respiratory syndrome coronavirus (MERS-CoV) are two highly transmissible and pathogenic viruses that emerged in humans at the beginning of the 21st century. Both viruses likely originated in bats, and genetically diverse coronaviruses that are related to SARS-CoV and MERS-CoV were discovered in bats worldwide. In this Review, we summarize the current knowledge on the origin and evolution of these two pathogenic coronaviruses and discuss their receptor usage; we also highlight the diversity and potential of spillover of bat-borne coronaviruses, as evidenced by the recent spillover of swine acute diarrhoea syndrome coronavirus (SADS-CoV) to pigs.


Assuntos
Coronavirus/genética , Coronavirus/patogenicidade , Variação Genética , Genoma Viral , Alphacoronavirus/genética , Alphacoronavirus/patogenicidade , Animais , Quirópteros/virologia , Infecções por Coronavirus , Evolução Molecular , Humanos , Coronavírus da Síndrome Respiratória do Oriente Médio/genética , Coronavírus da Síndrome Respiratória do Oriente Médio/patogenicidade , Filogenia , Vírus da SARS/genética , Vírus da SARS/patogenicidade , Síndrome Respiratória Aguda Grave , Suínos/virologia
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